Reactivation of the G1 enhancer landscape underlies core circuitry addiction to SWI/SNF.

Reactivation of the G1 enhancer landscape underlies core circuitry addiction to SWI/SNF.

Several cancer core regulatory circuitries (CRCs) depend on the sustained generation of DNA accessibility by SWI/SNF chromatin remodelers. However, the window when SWI/SNF is acutely essential in these settings has not been identified. Here we used neuroblastoma (NB) cells to model and dissect the relationship between cell-cycle progression and SWI/SNF ATPase activity. We find that SWI/SNF inactivation impairs coordinated occupancy of non-pioneer CRC members at enhancers within 1 hour, rapidly breaking their autoregulation. By precisely timing inhibitor treatment following synchronization, we show that SWI/SNF is dispensable for survival in S and G2/M, but becomes acutely essential only during G1 phase. We furthermore developed a new approach to analyze the oscillating patterns of genome-wide DNA accessibility across the cell cycle, which revealed that SWI/SNF-dependent CRC binding sites are enriched at enhancers with peak accessibility during G1 phase, where they activate genes involved in cell-cycle progression. SWI/SNF inhibition strongly impairs G1-S transition and potentiates the ability of retinoids used clinically to induce cell-cycle exit. Similar cell-cycle effects in diverse SWI/SNF-addicted settings highlight G1-S transition as a common cause of SWI/SNF dependency. Our results illustrate that deeper knowledge of the temporal patterns of enhancer-related dependencies may aid the rational targeting of addicted cancers.

若干癌症核心调控回路（CRC）依赖于SWI/SNF染色质重塑复合物对DNA可及性的持续产生。然而，在这些情况下SWI/SNF至关重要的关键时间窗口尚未被确定。在此我们利用神经母细胞瘤（NB）细胞来模拟和剖析细胞周期进程与SWI/SNF ATP酶活性之间的关系。我们发现SWI/SNF失活会在1小时内损害非先锋CRC成员在增强子上的协同占位，迅速打破它们的自我调节。通过在细胞同步化之后精确安排抑制剂处理的时间，我们表明SWI/SNF在S期和G2/M期对细胞存活是可有可无的，但仅在G1期是绝对必需的。我们还开发了一种新方法来分析全基因组DNA可及性在细胞周期中的波动模式，结果显示依赖于SWI/SNF的CRC结合位点在G1期可及性达到峰值的增强子处富集，它们在这些位点激活参与细胞周期进程的基因。SWI/SNF抑制强烈损害G1 - S期转换，并增强临床上使用的维甲酸诱导细胞周期退出的能力。在多种依赖SWI/SNF的不同情况下类似的细胞周期效应凸显出G1 - S期转换是对SWI/SNF依赖的一个常见原因。我们的研究结果表明，对增强子相关依赖的时间模式的更深入了解可能有助于对成瘾性癌症进行合理靶向治疗。